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A new study adds to the controversy surrounding the practice of giving antipsychotic drugs to Alzheimer disease (AD) patients. A clinical trial carried out under the auspices of the CATIE-AD (Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer Disease) Study Group suggests that the atypical or second-generation antipsychotics, olanzapine, quetiapine, and risperidone, are no better than placebo when given to AD patients. Results of the trial are published in yesterday’s New England Journal of Medicine.

About 50 percent of AD patients develop debilitating behavioral symptoms including anxiety, agitation, aggression, or psychoses such as hallucinations. These symptoms can have a significant impact on quality of life for the patients and can also put them and their caregivers and families at risk. Clinicians have grappled with how best to control these problems, and in many cases the answer has been to prescribe second-generation antipsychotics, which have been touted as being safer and more effective than the first generation of these drugs. The safety of this practice has already been called into question (see ARF related news story); now the efficacy seems suspect.

Lon Schneider, University of Southern California, and colleagues enrolled 421 outpatients with Alzheimer disease in a double-blind, placebo-controlled trial to test the effectiveness of the three medications. Patients were randomly assigned to olanzapine (n = 100), quetiapine (n = 94), risperidone (n = 85) or placebo (n = 142). To stimulate real-life conditions, doctors were allowed to adjust the “dose” by giving small and large capsules containing low and high amounts of drug or placebo.

The primary outcome measure was time to discontinuation for any reason, while secondary measures included improvement in the Clinical Global Impression of Change (CGIC) index at 12 weeks, and time to discontinuation for lack of efficacy or adverse events. The primary measure was chosen to reflect real-life conditions, and it relies on judgment calls of patients, caregivers, and clinicians as they weigh effectiveness, tolerability, and safety. As clinician Jason Karlawish, University of Pennsylvania, writes in an accompanying editorial, the study adhered to the “logic of clinical purpose,” which suggests that clinical trials be logically grounded in and ethically justified by the way in which they reflect and contribute to clinical practice. “The primary endpoint in the study by Schneider et al. is an accurate reflection of a clinical event: the decision to change treatment because the patient’s condition is worsening or not improving sufficiently,” Karlawish writes.

Unfortunately, there was no statistical difference in the logically grounded primary endpoints among the four treatment groups. Fifty percent of the quetiapine group stopped treatment by 5.3 weeks, while the olanzapine, risperidone, and placebo groups fared slightly though not statistically better with 50 percent dropout occurring at 8.1, 7.4, and 8.0 weeks, respectively. The secondary endpoints suggested that olanzapine and risperidone may be slightly better because average time to discontinuation due to lack of efficacy was 22.1 and 26.7 weeks for each, respectively, much longer than for quetiapine and placebo (9.1 and 9.0 weeks, respectively), suggesting improvement among some patients. However, any benefit from olanzapine and risperidone was offset by adverse events such as parkinsonism or extrapyramidal signs.

The study adds to growing concerns about the wisdom of using atypical antipsychotics, developed primarily for schizophrenia, to treat behavioral symptoms in elderly AD patients (see also earlier meta analysis by Schneider et al., 2006). In fact, as Karlawish points out in his editorial, the FDA labels for antipsychotic medications specifically state that they are not approved for the treatment of dementia-related psychosis and go so far as to put a “black-box” warning on the drugs.—Tom Fagan